NOS1-dependent negative feedback regulation of the epithelial sodium channel in the collecting duct

Kelly A. Hyndman, Vladislav Bugaj, Elena Mironova, James D. Stockand, Jennifer S. Pollock

Research output: Contribution to journalArticlepeer-review

36 Scopus citations


With an increase in urine flow there is a significant increase in shear stress against the renal epithelium including the inner medullary collecting duct, resulting in an increase in nitric oxide (NO) production. The mechanisms of the shear stress-mediated increases in NO are undetermined. Previous studies found that shear stress increases epithelial sodium channel (ENaC) open probability and endothelin (ET)-1 production in an ENaCdependent mechanism in the collecting duct (CD). Given that ET-1 stimulates NO production in the CD, we hypothesized that shear stress-induced NO production is downstream of shear stress-induced ENaC activation and ET-1 production in a negative feedback loop. We determined that nitric oxide synthase 1 (NOS1) and NOS3 contribute to shear stress-mediated NO production in the CD, that is attenuated by low doses of the ENaC inhibitors amiloride and benzamil. Moreover, ETB receptor blockade significantly blunted the shear stress-mediated NO production. We further elucidated whether mice lacking NOS1 in the collecting duct (CDNOS1KO) have an impaired renal ET-1 system in the CD. Although urinary ET-1 production and inner medullary ET receptor expression were similar between flox control and CDNOS1KO mice, acute ET-1 treatment significantly reduced ENaC open probability in CDs from flox mice but not CDNOS1KO mice compared with basal. Basal ENaC activity in CDs was similar between the genotypes. We conclude that during acute shear stress across the CD, ENaC acts in a negative feedback loop to stimulate NO production in an ETB/NOS1-dependent manner resulting in a decrease in ENaC open probability and promoting natriuresis.

Original languageEnglish (US)
Pages (from-to)F244-F251
JournalAmerican Journal of Physiology - Renal Physiology
Issue number3
StatePublished - 2015


  • Collecting duct
  • Epithelial sodium channel
  • Nitric oxide
  • Nitric oxide synthase

ASJC Scopus subject areas

  • Urology
  • Physiology


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